Friday, April 3, 2009

Heart Muscle Renewed Over Lifetime, Study Finds

Tests of nuclear weapons in the atmosphere, which lasted until 1963, generated a radioactive form of carbon, carbon-14. The carbon-14 in carbon dioxide is breathed in by plants, turned into glucose (see equation) and enters the human diet. In the body, the carbon-14 is incorporated into new DNA, and once a new cell is made, its DNA does not change. The level of carbon-14 in the atmosphere has dropped each year since 1963 (see graph), so the exact amount in a cell marks the year the cell was born. From a cell's birth date, researchers can calculate how quickly different tissues such as the intestine, brain and heart are renewed.

In a finding that may open new approaches to treating heart disease, Swedish scientists have succeeded in measuring a highly controversial property of the human heart: the rate at which its muscle cells are renewed during a person’s lifetime.

The finding upturns what has long been conventional wisdom: that the heart cannot produce new muscle cells and so people die with the same heart they were born with.

About 1 percent of the heart muscle cells are replaced every year at age 25, and that rate gradually falls to less than half a percent per year by age 75, concluded a team of researchers led by Dr. Jonas Frisen of the Karolinska Institute in Stockholm. The upshot is that about half of the heart’s muscle cells are exchanged in the course of a normal lifetime, the Swedish group calculates. Its results are to be published Friday in the journal Science.

“I think this will be one of the most important papers in cardiovascular medicine in years,” said Dr. Charles Murry, a heart researcher at the University of Washington in Seattle. “It helps settle a longstanding controversy about whether the human heart has any ability to regenerate itself.”

If the heart can generate new muscle cells, researchers can hope to develop drugs that might accelerate the process, since the heart fails to replace cells that are killed in a heart attack.

The dogma that the heart cannot generate new muscle cells has been challenged since 1987 by a somewhat lonely skeptic, Dr. Piero Anversa, now of the Harvard Medical School. Dr. Anversa maintains that heart muscle cells are renewed so fast that a person dying at age 80 has replaced the heart four times over. Many other researchers have doubted this assertion.

Cell turnover rates can easily be measured in animals by making their cells radioactive and seeing how fast they are replaced. Such an experiment, called pulse-labeling, could not ethically be done in people. But Dr. Frisen realized several years ago that nuclear weapons tested in the atmosphere until 1963 had in fact labeled the cells of the entire world’s population.

The nuclear blasts generated a radioactive form of carbon known as carbon-14. The amount of carbon-14 in the atmosphere has gradually diminished since 1963, when above-ground tests were banned, as it has been incorporated into plants and animals or diffused into the oceans.

In the body, carbon-14 in the diet gets into the DNA of new cells and stays unchanged for the life of the cell. Because the level of carbon-14 in the atmosphere falls each year, the amount of carbon-14 in the DNA can serve to indicate the cell’s birth date, Dr. Frisen found.

Four years ago he used his new method to assess the turnover rate of various tissues in the body, concluding that the average age of the cells in an adult’s body might be as young as 7 to 10 years. But there is a wide range of ages — from the rapidly turning over cells of the blood and gut to the mostly permanent cells of the brain.

Dr. Frisen has successfully applied his method to the heart muscle cells, but had to navigate a series of technical obstacles created by the special behavior of the cells. Many have two nuclei, instead of the usual one, and within these double nuclei the DNA may be duplicated again. “I was really impressed at the level of rigor they put into this analysis,” Dr. Murry said, calling it a “scientific tour de force.”

The finding that heart muscle cells do regenerate, though at a considerably slower rate than Dr. Anversa predicted, is a “reasonable conclusion to a hotly contested issue,” Dr. Murry said. “Anversa went out on a limb, and I think he was partly right.”

Dr. Loren Field, a heart expert at the Indiana University School of Medicine, said he had found that heart muscle cells regenerated in mice at the same rate that Dr. Frisen had found in people. Despite the controversy created by Dr. Anversa’s claims, there has long been agreement that there is a low but detectable rate of cell renewal in the heart, Dr. Field said. The goal now, in his view, is “to try to tickle the system to enhance it.”

Dr. Anversa, for his part, said he was “ecstatic” at Dr. Frisen’s confirmation of his view that the heart could generate new muscle cells, but suggested that the new measurements might have underestimated the rate at which new cells are formed. Since heart muscle cells contract 70 times a minute, they seem likely to need renewing more often than Dr. Frisen’s measurements suggest, he said. “Now let’s discuss the magnitude of the process, and that will let us think about how we can apply this concept to heart failure,” Dr. Anversa said.

Dr. Frisen said he did not agree that the rate of regeneration had been underestimated. He said it would now be worth trying to understand how the regeneration of heart muscle cells was regulated.

A zebrafish, for instance, can regenerate large regions of its heart after injury, and possibly a similar response could be induced in people. It could also be that the heart does generate many new muscle cells after a heart attack but that the cells fail to establish themselves. Drugs that kept any such new cells alive could be helpful, Dr. Frisen said.

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